Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet

Wellcome Trust Sanger Institute, Hinxton, UK.
Nature Genetics (Impact Factor: 29.35). 04/2009; 41(5):521-3. DOI: 10.1038/ng.349
Source: PubMed

ABSTRACT Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene.

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Available from: Giovanni Tonon, Sep 25, 2015
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    • "Although such mutations have not been reported so far in MM, EZH2 is clearly overexpressed in MM cells and contributes to cell survival [9]. This is consistent with data reporting the enrichment for H3K27me3 marked genes [10] as well as the finding of prevalent mutations of the H3K27-demethylase UTX [11] in MM cells. Although the functional role of EZH2 in maintaining the survival of MM cells is unknown, it has been shown that depletion of EZH2 could trigger apoptosis. "
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    ABSTRACT: Tumoral plasma cells has retained stemness features and in particular, a polycomb-silenced gene expression signature. Therefore, epigenetic therapy could be a mean to fight for multiple myeloma (MM), still an incurable pathology. Deazaneplanocin A (DZNep), a S-adenosyl-L-homocysteine hydrolase inhibitor, targets enhancer of zest homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2) and is capable to induce the death of cancer cells. We show here that, in some MM cell lines, DZNep induced both caspase-dependent and -independent apoptosis. However, the induction of cell death was not mediated through its effect on EZH2 and the trimethylation on lysine 27 of histone H3 (H3K27me3). DZNep likely acted through non-epigenetic mechanisms in myeloma cells. In vivo, in xenograft models, and in vitro DZNep showed potent antimyeloma activity alone or in combination with bortezomib. These preclinical data let us to envisage new therapeutic strategies for myeloma.
    PLoS ONE 09/2014; 9(9):e107009. DOI:10.1371/journal.pone.0107009 · 3.23 Impact Factor
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    • "Hence, understanding DNA methylation patterns is critical. Similarly, H3K27me3 is important to investigate because it has repeatedly been shown to be an powerful repressive epigenetic mark in promoters, the underlying enzymes controlling this mark are known to be dysregulated or mutated in many cancers [11], and changes in the distribution of this mark are important in differentiation of neural stem cells [12]. In some BTSCs, EZH2, a key member of the PRC2 complex that mediates the production of H3K27me3 marks, is upregulated and plays a pivotal role in glioblastoma tumor growth [13]. "
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    ABSTRACT: Background Aberrational epigenetic marks are believed to play a major role in establishing the abnormal features of cancer cells. Rational use and development of drugs aimed at epigenetic processes requires an understanding of the range, extent, and roles of epigenetic reprogramming in cancer cells. Using ChIP-chip and MeDIP-chip approaches, we localized well-established and prevalent epigenetic marks (H3K27me3, H3K4me3, H3K9me3, DNA methylation) on a genome scale in several lines of putative glioma stem cells (brain tumor stem cells, BTSCs) and, for comparison, normal human fetal neural stem cells (fNSCs). Results We determined a substantial “core” set of promoters possessing each mark in every surveyed BTSC cell type, which largely overlapped the corresponding fNSC sets. However, there was substantial diversity among cell types in mark localization. We observed large differences among cell types in total number of H3K9me3+ positive promoters and peaks and in broad modifications (defined as >50 kb peak length) for H3K27me3 and, to a lesser extent, H3K9me3. We verified that a change in a broad modification affected gene expression of CACNG7. We detected large numbers of bivalent promoters, but most bivalent promoters did not display direct overlap of contrasting epigenetic marks, but rather occupied nearby regions of the proximal promoter. There were significant differences in the sets of promoters bearing bivalent marks in the different cell types and few consistent differences between fNSCs and BTSCs. Conclusions Overall, our “core set” data establishes sets of potential therapeutic targets, but the diversity in sets of sites and broad modifications among cell types underscores the need to carefully consider BTSC subtype variation in epigenetic therapy. Our results point toward substantial differences among cell types in the activity of the production/maintenance systems for H3K9me3 and for broad regions of modification (H3K27me3 or H3K9me3). Finally, the unexpected diversity in bivalent promoter sets among these multipotent cells indicates that bivalent promoters may play complex roles in the overall biology of these cells. These results provide key information for forming the basis for future rational drug therapy aimed at epigenetic processes in these cells. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-724) contains supplementary material, which is available to authorized users.
    BMC Genomics 08/2014; 15(1):724. DOI:10.1186/1471-2164-15-724 · 3.99 Impact Factor
    • "In recent years, next-generation sequencing techniques have provided further insights into the genetics of RCC, highlighting several key biological themes through identification of somatic mutations of genes involved in sporadic RCC, particularly ccRCC. Notably, high frequencies of truncating somatic mutations in genes involved in chromatin modification have been demonstrated in several studies.[171819] In particular, involved genes included histone modifying genes PBRM1, SETD2, KDM5C, KDM6A and BAP1,[2021] and genes involved in the ubiquitin-mediated proteolysis pathway.[21] "
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    ABSTRACT: Advances in rationally targeted therapeutics over the last decade have transformed the clinical care of advanced kidney cancer. While oncologists consolidate the gains of the wave of new agents, comprising a panoply of anti-vascular endothelial growth factor multi-targeted tyrosine kinase inhibitors and inhibitors of the mammalian target of rapamycin (mTOR), there is an increasing sense that a plateau has been reached in the short term. It is sobering that all currently approved targeted therapies have not yielded durable remissions and remain palliative in intent. In the context of recent insights in kidney cancer biology, we review promising ongoing and future approaches for kidney cancer therapeutics aimed toward forging new paths in the systemic management of renal cell carcinoma. Broadly, candidate agents for such innovative strategies include immune check-point inhibitors, anti-cancer stem cell agents, next-generation anti-vascular endothelial growth factor receptor and anti-mTOR agents as well as more investigational agents in the preclinical and early clinical development settings.
    Journal of Carcinogenesis 02/2014; 13(1):3. DOI:10.4103/1477-3163.127638
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